Genetics & Clinical Cohorts

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To achieve a 95% reduction of TB deaths by 2035 the WHO END-TB strategy states that critical introduction of new tools, such as a vaccine, drugs and treatment regimes, and a point-of-care test are required. New tools to eliminate TB are reliant on new knowledge of TB. Here we are utilizing genomic technology to interrogate pathogen and host genomic variation in TB to advance our fundamental understanding of TB which is critically required to drive innovation for the design of new vaccines and drugs to control the TB epidemic. We will utilize our extensive clinical, epidemiological and genetic cohorts from Vietnam and Uganda which have been complied over the last 2 decades, to discover genetic determinants of TB disease, progression and outcome in humans and M.tuberculosis. We aim to 1/ identify genetic determinants of active pulmonary TB disease in humans and M.tb, 2/ identify genetic determinants in humans and M.tb associated with bacterial burden and poor disease outcome 3/ identify bacterial variants associated with transmission, using evolutionary and epidemiological signatures of transmission. In aims 1 and 2 we will utilize a paired host and pathogen genomic dataset from a large cohort of pulmonary TB patients, and analyze both host and pathogen genomic data individually and in combination. In these aims we will investigate host and pathogen gene variants associated with TB disease and clinical endpoints, as well as with “intermediate phenotypes” such as host control of bacterial replication, bacterial survival in the host, and bacterial clearance. In aim 3 we will use bacterial genome sequence to identify Mtb gene variants contributing to disease transmissibility by 1/ interrogating genomic signals of evolution and 2/ by utilizing epidemiological data of households with low and high TB transmission. The aims of core A Genetics will deliver gene discoveries to the 3 projects for functional analysis, while functional candidates identified in the 3 projects using in vitro and in vivo models will be assessed within our clinical cohorts to bridge the “investigative” gap between TB disease models and human TB disease. Through human and bacterial genomics, the outcome of core A will be the identification of key mechanisms in the response to Mtb infection, Mtb transmissibility, TB susceptibility and disease outcome. This research will have impact by advancing our fundamental understanding of TB which is essential to drive innovation for the future control of the TB epidemic.